期刊
COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s42003-021-02538-8
关键词
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资金
- Imaging Facility at Center for Life Nano Science, Istituto Italiano di Tecnologia
- Sapienza University
- Fondazione Istituto Italiano di Tecnologia
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti
- UK Medical Research Council [MR/M008606/1, MR/S006508/1, MR/S022708/1]
- Motor Neurone Disease Association [885-792]
- NIHR-UCLH Biomedical Research Centre
- Rosetrees Trust
The study found that mutations in the FUS gene are associated with ALS, affecting the activity of two RBPs related to neuronal RNA metabolism. Mutant FUS increases HuD protein levels by competing with FMRP for HuD mRNA binding, leading to excessive stability of its target gene transcript levels. Mutant FUS motoneurons exhibit increased axon branching and growth, potentially representing early events in ALS pathogenesis.
Mutations in the RNA-binding protein (RBP) FUS have been genetically associated with the motoneuron disease amyotrophic lateral sclerosis (ALS). Using both human induced pluripotent stem cells and mouse models, we found that FUS-ALS causative mutations affect the activity of two relevant RBPs with important roles in neuronal RNA metabolism: HuD/ELAVL4 and FMRP. Mechanistically, mutant FUS leads to upregulation of HuD protein levels through competition with FMRP for HuD mRNA 3'UTR binding. In turn, increased HuD levels overly stabilize the transcript levels of its targets, NRN1 and GAP43. As a consequence, mutant FUS motoneurons show increased axon branching and growth upon injury, which could be rescued by dampening NRN1 levels. Since similar phenotypes have been previously described in SOD1 and TDP-43 mutant models, increased axonal growth and branching might represent broad early events in the pathogenesis of ALS. Maria Giovanna Garone et al. use iPSC and mouse models to evaluate a mechanistic link between aberrant axonal phenotypes in ALS and the alteration of a cross-regulatory circuitry involving three RNA binding proteins: FUS, HuD and FMRP. Their results suggest NRN1 as a potential therapeutic target for ALS and provide further insight into the pathogenesis of this critical disorder.
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